(M1330-02-14) Continuous Manufacturing of Biological Drug Products for Pulmonary Drug Delivery

Purpose: The traditional approaches that are being used in formulation of dry powder inhalers (DPI) are spray drying and blending. In spray drying, active pharmaceutical ingredient (API) is encapsulated within an excipient which improves the physical and chemical stability of the API. However, spray drying has the potential for protein denaturation due to high temperature and shear. On the other hand, in blending, Once the drug and carrier have been prepared individually to their desired states, they are mixed until reaching a homogeneous concentration of drug on all the particles. nevertheless, both of these methods are used for batch production of DPI formulations, which can lead to potential downtime, increased setup times, and higher labor costs.

Methods: In this study, A novel lab-scale continuous manufacturing (CM) platform suitable for a variety of complex biopharmaceutical drug candidates for pulmonary drug delivery is designed, fabricated, and tested. This project facilitates the modernization of pharmaceutical manufacturing from the conventional batch-based method for the complex dosage forms for inhaled drug products. The robust and integrated CM platform comprised of electrospraying-based drying platform working in tandem with a customized conveyer belt to produce engineered drug particles (ordered or core-shell type mixtures) as the dry powder inhaler (DPI) formulation. The electrospray system comprised of a syringe pump and a high-voltage supplier modified to be a modular unit of the CM system.

Results: As a demonstration, microparticles containing bovine serum albumin (BSA) and insulin encapsulated in PLGA were fabricated and adhered to lactose carriers. Scanning electron microscopy (SEM) confirmed ~10 µm core–shell morphology, and fluorescence microscopy showed uniform protein distribution. Further characterization using Fourier-transform infrared (FTIR) spectroscopy and circular dichroism (CD) spectroscopy indicated an intact protein structure. Encapsulation efficiency and in vitro release were evaluated using UV–vis spectrophotometry, revealing approximately 78.2% encapsulation after formulation and nearly 75% cumulative release over three days.

Conclusion: It was concluded that the continuous manufacturing approach investigated here effectively addresses significant challenges encountered in traditional batch methods, including particle contamination, inadequate encapsulation control, and process scalability. Additionally, the integration of carrier and excipient components within DPI formulations, at same time, produced by this method enhanced powder flow properties, aerosolization performance, and deposition efficiency in respiratory tracts while protecting the API with encapsulation matrix. These results collectively demonstrate that electrospray-based continuous manufacturing provides an advantageous alternative technology for the large-scale production of stable and high-quality inhalable biologic products.

References: Mehta T, Najafian S, Patel K, Lacombe J, Chaudhuri B. Optimization of Carrier-Based Dry Powder Inhaler Performance: A Review 2025;17:96.
Xie J, Lim LK, Phua Y, Hua J, Wang C-H. Electrohydrodynamic atomization for biodegradable polymeric particle production 2006;302:103–12.
Zamani M, Prabhakaran MP, San Thian E, Ramakrishna S. Protein encapsulated core–shell structured particles prepared by coaxial electrospraying: Investigation on material and processing variables 2014;473:134–43.

Acknowledgements: The authors would like to acknowledge Office of the Vice President for Research of University of Connecticut for funding this project